In the body, axons are grouped together for most of their lengths in nerve bundles. In a single bundle, many different axons travel together, branching only near their target organs. Important properties of natural axonal activity include that: (a) each axon can fire independently of its neighbors in the bundle, and (b) each axon conveys action potentials in only one direction, either afferently (towards the brain) or efferently (towards its target organ). These two properties, however, are not properties of the axons themselves. The axons are only active cables emanating from neurons which can trigger action potentials in them. Since each axon can be connected to a different neuron, they can fire independently. Also, because the axons are connected to a neuron only on one side, they only convey action potentials away from the neuron.
When axons are activated artificially by simple stimulation of a nerve bundle, both of these properties of natural axonal activity are lost: entire regions of the bundle are activated simultaneously, and the axons fire in both directions at once, since the action potential is not triggered at only one of the ends of the axons. The loss of these properties causes the effect of artificial stimulation to be less natural, and may result in side effects, because axons in the bundle in addition to the target axon are indiscriminately activated. To overcome these shortcomings of simple stimulation, two stimulation techniques have been developed: selective stimulation and unidirectional stimulation.
Selective electrical stimulation of nerve fibers is the activation of small fibers in a nerve bundle without the activation of the large fibers. This is advantageous, for example, when the target organ is innervated only by small fibers. In addition, stimulation of large fibers can cause unwanted side effects (see, for example, Rijkhoff et al. (1994) and Jones J F et al., cited hereinbelow). Often, in addition to selective stimulation, it is also advantageous to stimulate unidirectionally such that only organs at one end of the nerve receive signals.
As defined by Rattay, in the article, “Analysis of models for extracellular fiber stimulation,” IEEE Transactions on Biomedical Engineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated herein by reference, the activation function (AF) of an unmyelinated axon is the second spatial derivative of the electric potential along an axon. In the region where the activation function is positive, the axon depolarizes, and in the region where the activation function is negative, the axon hyperpolarizes. If the activation function is sufficiently positive, then the depolarization will cause the axon to generate an action potential; similarly, if the activation function is sufficiently negative, then local blocking of action potentials transmission occurs. The activation function depends on the current applied, as well as the geometry of the electrodes and of the axon.
For a given electrode geometry, the equation governing the electrical potential is:∇(σ∇U)=4πj, 
where U is the potential, σ is the conductance tensor specifying the conductance of the various materials (electrode housing, axon, intracellular fluid, etc.), and j is a scalar function representing the current source density specifying the locations of current injection. The activation function is found by solving this partial differential equation for U. If an unmyelinated axon is defined to lie in the z direction, then the activation function is:
      A    ⁢                  ⁢    F    =                              ∂          2                ⁢        U                    ∂                  z          2                      .  
In a simple, illustrative example of a point electrode located a distance d from the axis of an axon in a uniformly-conducting medium with conductance a, the two equations above are solvable analytically, to yield:
            A      ⁢                          ⁢      F        =                            I          el                          4          ⁢          πσ                    ·                                    2            ⁢                          z              2                                -                      d            2                                                (                                          z                2                            +                              d                2                                      )                    2.5                      ,
where Iel is the electrode current. It is seen that when a and d are held constant, and for a constant positive Iel (to correspond to anodal current), the minimum value of the activation function is negative, and is attained at z=0, i.e., at the point on the nerve closest to the source of the anodal current. Thus, the most negative point on the activation function corresponds to the place on a nerve where hyperpolarization is maximized, namely at the point on the nerve closest to the anode.
Additionally, this equation predicts positive “lobes” for the activation function on either side of z=0, these positive lobes peaking in their values at a distance which is dependent on each of the other parameters in the equation. The positive values of the activation function correspond to areas of depolarization, a phenomenon typically associated with cathodic current, not anodal current. However, it has been shown that excess anodal current does indeed cause the generation of action potentials adjacent to the point on a nerve corresponding to z=0, and this phenomenon is therefore called the “virtual cathode effect.” (An analogous, but reverse phenomenon, the “virtual anode effect” exists responsive to excess cathodic stimulation.)
The Rattay article also describes techniques for calculating the activation function for nerves containing myelinated axons. The activation function in this case varies as a function of the diameter of the axon in question. Thus, the activation function calculated for a 1 micron diameter myelinated axon is different from the activation function calculated for a 10 micron diameter axon.
U.S. Pat. No. 6,684,105 to Cohen et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus comprising an electrode device adapted to be coupled to longitudinal nervous tissue of a subject, and a control unit adapted to drive the electrode device to apply to the nervous tissue a current which is capable of inducing action potentials that propagate in the nervous tissue in a first direction, so as to treat a condition. The control unit is further adapted to suppress action potentials from propagating in the nervous tissue in a second direction opposite to the first direction.
U.S. Pat. No. 6,907,295 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for applying current to a nerve. A cathode is adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve. A primary inhibiting anode is adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve. A secondary inhibiting anode is adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site.
A number of patents and articles describe methods and devices for stimulating nerves to achieve a desired effect. Often these techniques include a design for an electrode or electrode cuff.
U.S. Pat. No. 4,608,985 to Crish et al. and U.S. Pat. No. 4,649,936 to Ungar et al., which are incorporated herein by reference, describe electrode cuffs for selectively blocking orthodromic action potentials passing along a nerve trunk, in a manner intended to avoid causing nerve damage.
PCT Patent Publication WO 01/10375 to Felsen et al., which is incorporated herein by reference, describes apparatus for modifying the electrical behavior of nervous tissue. Electrical energy is applied with an electrode to a nerve in order to selectively inhibit propagation of an action potential.
U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated herein by reference, describes techniques for selectively blocking different size fibers of a nerve by applying direct electric current between an anode and a cathode that is larger than the anode.
U.S. Pat. No. 5,824,027 Hoffer et al., which is incorporated herein by reference, describes a nerve cuff having one or more sets of electrodes for selectively recording electrical activity in a nerve or for selectively stimulating regions of the nerve. Each set of electrodes is located in a longitudinally-extending chamber between a pair of longitudinal ridges which project into the bore of the nerve cuff. The ridges are electrically insulating and serve to improve the selectivity of the nerve cuff. The ridges seal against an outer surface of the nerve without penetrating the nerve. In an embodiment, circumferential end sealing ridges extend around the bore at each end of the longitudinal ridges, and are described as enhancing the electrical and/or fluid isolation between different ones of the longitudinally-extending chambers.
U.S. Pat. No. 4,628,942 to Sweeney et al., which is incorporated herein by reference, describes an annular electrode cuff positioned around a nerve trunk for imposing electrical signals on to the nerve trunk for the purpose of generating unidirectionally propagated action potentials. The electrode cuff includes an annular cathode having a circular passage therethrough of a first diameter. An annular anode has a larger circular passage therethrough of a second diameter, which second diameter is about 1.2 to 3.0 times the first diameter. A non-conductive sheath extends around the anode, cathode, and nerve trunk. The anode and cathode are placed asymmetrically to one side of the non-conductive sheath.
U.S. Pat. No. 5,423,872 to Cigaina, which is incorporated herein by reference, describes a process for treating obesity and syndromes related to motor disorders of the stomach of a patient. The process consists of artificially altering, by means of sequential electrical pulses and for preset periods of time, the natural gastric motility of the patient to prevent emptying or to slow down gastric transit. The '872 patent describes an electrocatheter adapted to be coupled to a portion of the stomach. A portion of the electrocatheter has a rough surface for producing a fibrous reaction of the gastric serosa, in order to contribute to the firmness of the anchoring.
U.S. Pat. No. 4,573,481 to Bullara, which is incorporated herein by reference, describes an implantable helical electrode assembly, configured to fit around a nerve, for electrically triggering or measuring an action potential or for blocking conduction in nerve tissue. A tissue-contacting surface of each electrode is roughened to increase the electrode surface area.
The following patents, which are incorporated herein by reference, may be of interest:    U.S. Pat. No. 6,230,061 to Hartung    U.S. Pat. No. 5,282,468 to Klepinski    U.S. Pat. No. 4,535,785 to van den Honert et al.    U.S. Pat. No. 5,215,086 to Terry et al.    U.S. Pat. No. 6,341,236 to Osorio et al.    U.S. Pat. No. 5,487,756 to Kallesoe et al.    U.S. Pat. No. 5,634,462 to Tyler et al.    U.S. Pat. No. 6,456,866 to Tyler et al.    U.S. Pat. No. 4,602,624 to Naples et al.    U.S. Pat. No. 6,600,956 to Maschino et al.    U.S. Pat. No. 5,199,430 to Fang et al.
The following articles, which are incorporated herein by reference, may be of interest:    Ungar I J et al., “Generation of unidirectionally propagating action potentials using a monopolar electrode cuff,” Annals of Biomedical Engineering, 14:437-450 (1986)    Sweeney JD et al., “An asymmetric two electrode cuff for generation of unidirectionally propagated action potentials,” IEEE Transactions on Biomedical Engineering, vol. BME-33(6) (1986)    Sweeney JD et al., “A nerve cuff technique for selective excitation of peripheral nerve trunk regions,” IEEE Transactions on Biomedical Engineering, 37(7) (1990)    Naples GG et al., “A spiral nerve cuff electrode for peripheral nerve stimulation,” by IEEE Transactions on Biomedical Engineering, 35(11) (1988)    van den Honert C et al., “Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli,” Science, 206:1311-1312 (1979)    van den Honert C et al., “A technique for collision block of peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans. Biomed. Eng. 28:373-378 (1981)    van den Honert C et al., “A technique for collision block of peripheral nerve: Frequency dependence,” MP-12, IEEE Trans. Biomed. Eng. 28:379-382 (1981)    Rijkhoff N J et al., “Acute animal studies on the use of anodal block to reduce urethral resistance in sacral root stimulation,” IEEE Transactions on Rehabilitation Engineering, 2(2):92-99 (1994)    Mushahwar V K et al., “Muscle recruitment through electrical stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil Eng, 8(1):22-9 (2000)    Deurloo K E et al., “Transverse tripolar stimulation of peripheral nerve: a modelling study of spatial selectivity,” Med Biol Eng Comput, 36(1):66-74 (1998)    Tarver W B et al., “Clinical experience with a helical bipolar stimulating lead,” Pace, Vol. 15, October, Part II (1992)    Hoffer J A et al., “How to use nerve cuffs to stimulate, record or modulate neural activity,” in Neural Prostheses for Restoration of Sensory and Motor Function, Chapin J K et al. (Eds.), CRC Press (1st edition, 2000)    Jones J F et al., “Heart rate responses to selective stimulation of cardiac vagal C fibres in anaesthetized cats, rats and rabbits,” J Physiol 489(Pt 1):203-14 (1995)    Evans M S et al., “Intraoperative human vagus nerve compound action potentials,” Acta Neurol Scand 110:232-238 (2004)
In physiological muscle contraction, nerve fibers are recruited in the order of increasing size, from smaller-diameter fibers to progressively larger-diameter fibers. In contrast, artificial electrical stimulation of nerves using standard techniques recruits fibers in a larger- to smaller-diameter order, because larger-diameter fibers have a lower excitation threshold. This unnatural recruitment order causes muscle fatigue and poor force gradation. Techniques have been explored to mimic the natural order of recruitment when performing artificial stimulation of nerves to stimulate muscles.
Fitzpatrick et al., in “A nerve cuff design for the selective activation and blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. in Medicine and Biology Soc, 13(2), 906 (1991), which is incorporated herein by reference, describe a tripolar electrode used for muscle control. The electrode includes a central cathode flanked on its opposite sides by two anodes. The central cathode generates action potentials in the motor nerve fiber by cathodic stimulation. One of the anodes produces a complete anodal block in one direction so that the action potential produced by the cathode is unidirectional. The other anode produces a selective anodal block to permit passage of the action potential in the opposite direction through selected motor nerve fibers to produce the desired muscle stimulation or suppression.
The following articles, which are incorporated herein by reference, may be of interest:    Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acute rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology Soc., 20(5):2564 (1998)    Rijkhoff N J et al., “Selective stimulation of small diameter nerve fibers in a mixed bundle,” Proceedings of the Annual Project Meeting Sensations/Neuros and Mid-Term Review Meeting on the TMR-Network Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)    Baratta R et al., “Orderly stimulation of skeletal muscle motor units with tripolar nerve cuff electrode,” IEEE Transactions on Biomedical Engineering, 36(8):836-43 (1989)
The following articles, which are incorporated herein by reference, describe techniques using cuff electrodes to selectively excite peripheral nerve fibers distant from an electrode without exciting nerve fibers close to the electrode:    Grill WM et al., “Inversion of the current-distance relationship by transient depolarization,” IEEE Trans Biomed Eng, 44(1):1-9 (1997)    Goodall EV et al., “Position-selective activation of peripheral nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng, 43(8):851-6 (1996)    Veraart C et al., “Selective control of muscle activation with a multipolar nerve cuff electrode,” IEEE Trans Biomed Eng, 40(7):640-53 (1993)
One method used for selective stimulation is based on the observation that the stimulation/block threshold of fibers is inversely proportional to their radius. Thus, to stimulate only small fibers, all fibers are stimulated using a large cathodic current, and the large fibers are then blocked using a smaller anodal current, the net effect being action potential propagation in the small fibers only. To achieve unidirectional stimulation, one uses larger anodic currents on one side, thus blocking all fibers on that side. Because of the intrinsic physiological timescales of the ion channels in the axon, to block an action potential one uses a long pulse of approximately 1 millisecond. This long pulse may degrade stimulation efficiency. By comparison, an action potential can be triggered with pulses as short as approximately 10 microseconds.
A method for selective stimulation is described in Lertmanorat Z et al., “A novel electrode array for diameter-dependent control of axonal excitability: a simulation study,” IEEE Transactions on Biomedical Engineering 51(7):1242-1250 (2004), which is incorporated herein by reference. The described Electrode Array Selective Stimulation (EASS) method relies on the structure of myelinated fibers and employs electrode arrays. The myelinated fibers are surrounded by a sheath of myelin, which functions as an isolator. In this sheath there are gaps at regular intervals, called nodes of Ranvier. The gap distance is roughly proportional to the radius of the axon. Ion channels are present only at these gaps.
The principle of EASS is that if an electric field is produced which is periodic along a nerve, and the period matches the gap distance of an axon with a certain diameter, then the axon essentially “sees” a constant electric field, so that no stimulation/block occurs. Axons of different gap-distances see a varying field and are thus stimulated/blocked. The variation in the electric field that an axon “sees” depends on the ratio between its gap distance and the field period. The variation also depends on the radial distance (depth) from the electrode to the axon. As the axon gets further away from the electrode, the field becomes less varying since the cathodic and anodal fields tend to cancel each other. The inventors of the present patent application estimate that the fields vary in a substantial manner up to a radial distance of about one period of the field. It should be noted that at all distances, the field has the same periodicity. Therefore, axons with a nodal gap distance which matches the field period will not be activated at any depth, but other axons may not be activated because the field becomes too weak.
Since the gap distance is proportional to the axon radius, by selecting a period for the field to change, a range of axon radii can be selected which are substantially not affected by the electric field. Setting the period of the field to be the gap distance of large fibers ensures that large fibers will not be affected by the stimulation. An advantage of this method for selective stimulation is that stimulus duration can be short; no blocking is needed since the large fibers are simply not activated.
An EASS electrode can be made by placing an alternating series of anode and cathodes along the axon, spaced a gap width apart. The cathodes and anodes can be ring shaped to give better field uniformity inside the nerve.
The main shortcoming of this method is that while it enables selective stimulation with short pulses, it does not provide unidirectional stimulation.